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Introduction to Pharmaceutical Freeze Drying

David Debo, PE

Date ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 1 Agenda

• Introduction • Stages of the process • System components

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 2 Introduction

• What is lyophilization? • What is sublimation? • Why freeze dry? • What are the major phases of freeze drying? • What components are used in freeze drying?

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 3 Introduction

• What is lyophilization? – The process of isolating a substance from solution by freezing the solution and vaporizing the ice away under vacuum conditions. Also called freeze-drying

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 4 Introduction

• What is sublimation? – The process of changing from a solid to a gas without passing through an intermediate phase.

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 5 Introduction

• Some Commonly Freeze Dried Materials – Bacteria – Viruses – Vaccines – Plasma – Small Zoological Specimens – Fruit – Coffee

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Introduction – What is Freeze Dried

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 7 Introduction - History

• Ancient Inca – Natural freeze drying potatoes and meat • Modern freeze drying progressed during World War II – Blood plasma

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 8 Introduction - Advantages

• The advantages of lyophilization include: – Ease of processing a liquid, which simplifies aseptic handling – Enhanced stability of a dry powder – Removal of water without excessive heating of the product – Enhanced product stability in a dry state – Rapid and easy dissolution of reconstituted product

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Introduction - Disadvantages

• Disadvantages of lyophilization include: – Increased handling and processing time – Need for sterile diluent upon reconstitution – Cost and complexity of equipment

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Why Freeze Dry - Pharmaceuticals

• Increase the shelf life of the products, such as vaccines and other injectables. • Produce tablets or wafers

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 11 Phases of the process

• Three main process phases: – Freezing – Primary drying: ‘sublimation’ – Secondary drying: removal of absorbed water ‘desorption’

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 12 for Water

760 14.7 1000 Freezing Liquid Solid 76 1.45 100 (ice) Condensation

7.6 0.145 10 Vapour Sublimation

0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC)

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Phase Diagram for Water Freezing

760 14.7 1000 Liquid Solid 76 1.45 100 (ice)

7.6 0.145 10 Vapour

0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC)

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Phase Diagram for Water Evacuation

760 14.7 1000 Liquid Solid 76 1.45 100 (ice)

7.6 0.145 10 Vapour

0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC)

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Phase Diagram for Water Drying

760 14.7 1000 Liquid Solid 76 1.45 100 (ice)

7.6 0.145 10 Vapour

0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC)

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Phase Diagram for Water

760 14.7 1000 Liquid Solid 76 1.45 100 (ice)

7.6 0.145 10 Vapour

0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC)

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Introduction – Dried Product

• Sections of freeze dried material showing voids remaining after sublimation

DIRECTION OF HEAT REMOVAL DURING FREEZING COMPACT SOLID RESIDUE DRY MATERIAL DRY MATERIAL

CHANNELS LEFT TRANSITION IN ICE STRUCTURE BY SUBLIMED ICE DURING FREEZING

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freezing

• Definition – Reduction of temperature to induce of the bulk of the contained water • Purpose – Prevents frothing when vacuum is applied – Prevents Shrinkage (retention of form) – Prevents concentration of – Minimizes temperature dependent reactions

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 19 Freezing

Solute “Freezing”

60 C

Temperature of solution is lowered until the freezes

0 C Note that the product is not frozen at this time Temperature of solution is lowered further until the product “freezes”

-60 C

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freezing

chamber shelves condenser product- pressure temperature temperature temperature 14.7 PSI -40.0ºC Ambient -40.0ºC

duration of process step: ± 2 hr

fluid frozen product product

shelf at intense cooled room temperature shelf

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freezing – Controlled Nucleation

• Controlled nucleation ensures uniformity in freezing and thus uniformity in drying

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 22 Primary Drying

• Definition: – The sublimation phase • Purpose: – Removal of Ice with minimum harm to the product – Note: Primary drying is complete when all ice has disappeared. Some moisture remains “bound” to or adsorbed by the apparently dry product.

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Primary Drying

Primary Drying

0 Bar 1 Bar

60 C

The atmosphere in and around the vial is removed

Heat is applied to the 0 C product

Water vapor (gas phase) is evolved The product matrix is left -60 C behind

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Primary Drying

chamber shelves condenser product- pressure temperature temperature temperature Ambient 200 µ -40 →+20 ºC → → -50ºC -40 -20 ºC

water vapor duration of process step: ± 10 hrs removal

glass sublimation front vial moves towards vial bottom and core as dried drying proceeds product

frozen conduction heat product through vial

drying ‘completely dried’ product (up to 95%)

powerful heated shelf ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Primary Drying

heated shelf (at + 500 C)

possible temperature-curve in a vial + glass of vial -25 -20 25

dry product frozen interface between dry and frozen product is frozen product moving downwards + -25 -20 -10 0 + + +30 +40 +50 25 10 20

0 heated shelf (at + 500 C) temperature (c)

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Secondary Drying

• Definition: – Desorption of moisture remaining after primary drying • Purpose: – To reduce the residual moisture content of primary freeze-dried material to improve stability and shelf life.

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Secondary Drying

Secondary Drying

0 Bar 1 Bar

60 C Additional Heat is applied to the product

“Bound” water is removed

0 C A dry product matrix is left behind

-60 C

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Secondary Drying

chamber shelves condenser product- pressure temperature temperature temperature 25 µ +20 →+35 ºC -50 → -70 ºC -20 → +30 ºC

duration of process step: ±±± 3...12 hrs water vapor removal glass adsorbed vial moisture adsorbed moisture dried product conduction heat through vial

drying completely dried product (up to 98%)

heated shelf increased heated shelf

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Venting

• Purpose: – To raise the pressure in the product chamber for stoppering and unloading.

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Stoppering

• Purpose: – To force the stoppers into the vial prior to unloading.

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Stoppering

Stoppering Ram

Bellows Compressed

Chamber

Bellows Extended

Stoppering Bellows Operation

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Stoppering

chamber shelves condenser product- pressure temperature temperature temperature 12.0 PSI +18 ºC off +25 ºC

duration of process step: ± 3 mins

stopper on vial stopper is fully with vent open closing the vial

shelf at room temperature

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Basic Freeze Dryer Components

• Product Chamber • Ice Condenser • Vacuum System • Refrigeration System

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Simple Freeze Drying Apparatus

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Basic Elements

Product Chamber Ice Condenser

Refrigeration System Vacuum System

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Laboratory Scale Freeze Drying

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Pilot and Production Equipment

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Techniques used

• Refrigeration • Heating • Vacuum • Control – Time – Temperature – Pressure

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Refrigeration - Compressor

• Reciprocating Compressor

• Screw Compressor

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Refrigeration – Liquid Nitrogen

Liquid Nitrogen 3.4 Kg/sec LN 2 Inlet 1.1 MPa Absorbed 2.4 Kg/sec Heat

N2 Gas Exhaust 0.7 MPa

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Drying Technology Shelf Heating and Cooling

Silicone Oil Heat Exchangers

Silicone Oil Heater

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Shelves

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Shelf Construction

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Shelf Construction

Fusion Welded

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Sub Systems - Heating (Shelves) heating system product- distributor shelf

(part of) cooling system

to ice condenser

piping filled with silicone oil

piping filled with refrigerant circulation electrical heat compressor pump heater exchanger

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer

Chambe r Condenser

Vapor

Heat Exchanger

Vacuum Heater Pump Compresso r #2 Condenser Cooling SublimationDesorptionFreezing Compressor Evacuation #1

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Vacuum Pumps

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Vacuum Control

• Two Methods of Control Modulating valve • Calibrated Leak used in calibrated leak – Preferred method! – Uses an MKS electronically controlled needle valve to bleed inert gas into chamber • Vacuum Valve Control – Not common in Europe or America, Mostly in Japan. – Allows for vacuum sweep control. ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Vacuum control

• Initial part of drying – Higher concentration of water vapor – Less calibrated leak

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 50 Vacuum control

• End of drying – Less water vapor – More calibrated leak

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 51 Typical process schedule

• 1 CIP • 7 Secondary Dry • 2 Sterilize • 8 Pre-aerate • 3 Leak test • 9 Stopper – system and bellows • 10 Aerate • 4 Load • 11 Unload • 5 Freeze • 12 Defrost • 6 Primary Dry

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Typical Freeze Dryer Features

• 316 SS Product Chamber • Fluid Circulated Product Shelves • Hydraulic Stoppering Mechanism • Refrigeration System • Vacuum Pumping System • Isolation Valve Between Chamber and Condenser • Clean in Place and Steam Clean Option

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS SCADA – User Interface

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Evaluation Questions

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 60 Questions & Thank you

– David Debo, PE – Engineering Manager – IMA LIFE – 2175 Military Rd. – Tonawanda, NY – [email protected] – Office: 716-695-6354, ext. 1101 – Cell: 716-564-7180

ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS